The proposed studies will use innovative approaches to expand upon our knowledge of lung stem cells to broaden treatment paradigms for NHLBI-related lung diseases. We therefore hypothesize that the maintenance of lung MSC function by Wnt/-catenin signaling is necessary for pulmonary tissue homeostasis. We propose to examine lung MSC-dependent mechanisms of abnormal pulmonary architecture and function using novel mouse models both in vitro and in vivo. We will determine the mechanism by which adult lung MSCs contribute to pulmonary tissue architecture and function in vivo. In addition, we will determine the mechanism by which Wnt/-catenin signaling regulates lung MSCs function and affects tissue homeostasis using both in vitro and in vivo novel systems. These models will enable us to identify a cell type which may be suited as a therapeutic target. Additionally, these studies will generate important resources and reagents that will be of vast interest to both the scientific and medical communities.